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Association of Childhood Infection With IQ and Adult Nonaffective Psychosis in Swedish Men: A Population-Based Longitudinal Cohort and Co-relative Study.

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Khandaker, Golam M 
Dalman, Christina 
Kappelmann, Nils 
Dal, Henrik 


Importance: Associations between childhood infection, IQ, and adult nonaffective psychosis (NAP) are well established. However, examination of sensitive periods for exposure, effect of familial confounding, and whether IQ provides a link between childhood infection and adult NAP may elucidate pathogenesis of psychosis further. Objectives: To test the association of childhood infection with IQ and adult NAP, to find whether shared familial confounding explains the infection-NAP and IQ-NAP associations, and to examine whether IQ mediates and/or moderates the childhood infection-NAP association. Design, Setting, and Participants: Population-based longitudinal cohort study using linkage of Swedish national registers. The risk set included all Swedish men born between 1973 and 1992 and conscripted into the military until the end of 2010 (n = 771 698). We included 647 515 participants in the analysis. Measurement of Exposures: Hospitalization with any infection from birth to age 13 years. Main Outcomes and Measures: Hospitalization with an International Classification of Diseases diagnosis of NAP until the end of 2011. At conscription around age 18 years, IQ was assessed for all participants. Results: At the end of follow-up, the mean (SD) age of participants was 30.73 (5.3) years. Exposure to infections, particularly in early childhood, was associated with lower IQ (adjusted mean difference for infection at birth to age 1 year: -1.61; 95% CI, -1.74 to -1.47) and with increased risk of adult NAP (adjusted hazard ratio for infection at birth to age 1 year: 1.19; 95% CI, 1.06 to 1.33). There was a linear association between lower premorbid IQ and adult NAP, which persisted after excluding prodromal cases (adjusted hazard ratio per 1-point increase in IQ: 0.976; 95% CI, 0.974 to 0.978). The infection-NAP and IQ-NAP associations were similar in the general population and in full-sibling pairs discordant for exposure. The association between infection and NAP was both moderated (multiplicative, β = .006; SE = 0.002; P = .02 and additive, β = .008; SE = 0.002; P = .001) and mediated (β = .028; SE = 0.002; P < .001) by IQ. Childhood infection had a greater association with NAP risk in the lower, compared with higher, IQ range. Conclusions and Relevance: Early childhood is a sensitive period for the effects of infection on IQ and NAP. The associations of adult NAP with early-childhood infection and adolescent IQ are not fully explained by shared familial factors and may be causal. Lower premorbid IQ in individuals with psychosis arises from unique environmental factors, such as early-childhood infection. Early-childhood infections may increase the risk of NAP by affecting neurodevelopment and by exaggerating the association of cognitive vulnerability with psychosis.



Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Correlation of Data, Hospitalization, Humans, Infant, Infant, Newborn, Infections, Intelligence, Longitudinal Studies, Male, Psychotic Disorders, Registries, Risk Factors, Socioeconomic Factors, Sweden, Young Adult

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JAMA Psychiatry

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American Medical Association
National Institute for Health Research (NIHR) (via Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) (unknown)
Academy of Medical Sciences (unknown)
Wellcome Trust (201486/Z/16/Z)
Wellcome Trust (095844/Z/11/Z)
Wellcome Trust (088869/Z/09/Z)
National Institute for Health Research (NIHR) (via Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) (RP PG-0616-20003)
Dr Khandaker is supported by an Intermediate Clinical Fellowship from the Wellcome Trust (201486/Z/16/Z) and a Clinical Lecturer Starter Grant from the Academy of Medical Sciences, UK (80354). Dr Jones reports having grant support from the Wellcome Trust (095844/Z/11/Z and 088869/Z/09/Z) and from the National Institute for Health Research: RP-PG-0616-20003, Cambridge Biomedical Research Centre and Collaboration for Leadership in Applied Health Research and Care East of England. Dr Dalman reports grant support from the Swedish Research Council. Dr Karlsson reports grant support from the Stanley Medical Research Institute.